tbuckley/cabot-search huggingface dataset:
Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus
Authors: Warren Floyd, Matthew Pierpoint, Chang Su, Rutulkumar Patel, Lixia Luo, Katherine Deland, Amy J. Wisdom, Daniel Zhu, Yan Ma, Suzanne Bartholf DeWitt, Nerissa T. Williams, Alexander L. Lazarides, Jason A. Somarelli, David L. Corcoran, William C. Eward, Diana M. Cardona, David G. Kirsch
Journal: Journal of Clinical Investigation (2023)

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes.
Correction: Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease
Authors: Gabriella Assante, Sriram Chandrasekaran, Stanley Ng, Aikaterini Tourna, Carolina H. Chung, Kowsar A. Isse, Jasmine L. Banks, Ugo Soffientini, Celine Filippi, Anil Dhawan, Mo Liu, Steven G. Rozen, Matthew Hoare, Peter Campbell, J. William O. Ballard, Nigel Turner, Margaret J. Morris, Shilpa Chokshi, Neil A. Youngson
Journal: Genome Medicine (2023)
The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression
Authors: Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K. Mookhtiar, Kranthi Kunkalla, Alfredo M. Valencia, Clayton K. Collings, Cigall Kadoch, Francisco Vega, Scott C. Kogan, Ramin Shiekhattar, Lluis Morey, Daniel Bilbao, Stephen D. Nimer
Journal: Journal of Clinical Investigation (2023)

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.
Letter to the Editor: Concurrent large spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: A randomized controlled trial
Authors: Hong-Jing Yin, Yue-Meng Wan
Journal: Hepatology (2023)

Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, China, 650101 Author disclosures: None; Financial disclosures: None Funding: The Yunnan Science and Technology Department Fund (Grant No. 7012302106). Abbreviations: portal venous pressure declines (PVDs); spontaneous portosystemic shunt (SPSS); Transjugular intrahepatic portosystemic shunt (TIPS) Correspondence Yue-Meng Wan, Kunming Medical University Second Affliated Hospital, gastroenterology department II or hepatology center. Email: [email protected]
Deciphering the role of soluble ORF2 protein in virus-host interaction in HEV infection
Authors: Michelle Maas, Christoph Neumann-Haefelin
Journal: Hepatology (2023)

Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany Funding information: Christoph Neumann-Haefelin is funded by grants from the German Research Foundation (DFG; SFB1160, project number 256073931). Editorial for HEP-22-1806.R2: 'Soluble ORF2 protein enhances HEV replication and induced long-lasting antibody response and protective immunity in vivo' by Ralfs et al. Correspondence Christoph Neumann-Haefelin, MD, Department of Medicine II, Medical Center, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. Email: [email protected]
Titanium-Nitride-Oxide–Coated vs Everolimus-Eluting Stents in Acute Coronary Syndrome
Authors: Frederic Bouisset, Jussi Sia, Takuya Mizukami, Pasi P. Karjalainen, Pim A. L. Tonino, Nico H. J. Pijls, Jan Van der Heyden, Hannu Romppanen, Kari Kervinen, Juhani K. E. Airaksinen, Jacques Lalmand, Peter Frambach, Bruno Roza da Costa, Carlos Collet, Bernard De Bruyne
Journal: JAMA Cardiology (2023)

Titanium-nitride-oxide (TiNO)-coated stents show faster strut coverage compared with drug-eluting stents without excessive intimal-hyperplasia observed in bare metal stents. It is important to study long-term clinical outcomes after treatment of patients with an acute coronary syndrome (ACS) by TiNO-coated stents, which are neither drug-eluting stents nor bare metal stents.
A motor association area in the depths of the central sulcus
Authors: Michael A. Jensen, Harvey Huang, Gabriela Ojeda Valencia, Bryan T. Klassen, Max A. van den Boom, Timothy J. Kaufmann, Gerwin Schalk, Peter Brunner, Gregory A. Worrell, Dora Hermes, Kai J. Miller
Journal: Nature Neuroscience (2023)

Abstract Cells in the precentral gyrus directly send signals to the periphery to generate movement and are principally organized as a topological map of the body. We find that movement-induced electrophysiological responses from depth electrodes extend this map three-dimensionally throughout the gyrus. Unexpectedly, this organization is interrupted by a previously undescribed motor association area in the depths of the midlateral aspect of the central sulcus. This ‘Rolandic motor association’ (RMA) area is active during movements of different body parts from both sides of the body and may be important for coordinating complex behaviors.
Reconsidering the route of drug delivery in refractory multiple sclerosis: Toward a more effective drug accumulation in the central nervous system
Authors: Lukasz Kalkowski, Piotr Walczak, Marcin P. Mycko, Izabela Malysz‐Cymborska
Journal: Medicinal Research Reviews (2023)

Multiple sclerosis is a chronic demyelinating disease with different disease phenotypes. The current FDA-approved disease-modifying therapeutics (DMTs) cannot cure the disease, but only alleviate the disease progression. While the majority of patients respond well to treatment, some of them are suffering from rapid progression. Current drug delivery strategies include the oral, intravenous, subdermal, and intramuscular routes, so these drugs are delivered systemically, which is appropriate when the therapeutic targets are peripheral. However, the potential benefits may be diminished when these targets sequester behind the barriers of the central nervous system. Moreover, systemic drug administration is plagued with adverse effects, sometimes severe. In this context, it is prudent to consider other drug delivery strategies improving their accumulation in the brain, thus providing better prospects for patients with rapidly progressing disease course. These targeted drug delivery strategies may also reduce the severity of systemic adverse effects. Here, we discuss the possibilities and indications for reconsideration of drug delivery routes (especially for those "non-responding" patients) and the search for alternative drug delivery strategies. More targeted drug delivery strategies sometimes require quite invasive procedures, but the potential therapeutic benefits and reduction of adverse effects could outweigh the risks. We characterized the major FDA-approved DMTs focusing on their therapeutic mechanism and the potential benefits of improving the accumulation of these drugs in the brain.
Global synergistic actions to improve brain health for human development
Authors: Mayowa O. Owolabi, Matilde Leonardi, Claudio Bassetti, Joke Jaarsma, Tadeusz Hawrot, Akintomiwa I. Makanjuola, Rajinder K. Dhamija, Wuwei Feng, Volker Straub, Jennifer Camaradou, David W. Dodick, Rosita Sunna, Bindu Menon, Claire Wright, Chris Lynch, Antonella Santuccione Chadha, Maria Teresa Ferretti, Anna Dé, Coriene E. Catsman-Berrevoets, Muthoni Gichu, Cristina Tassorelli, David Oliver, Walter Paulus, Ramla K. Mohammed, Augustina Charway-Felli, Kevin Rostasy, Valery Feigin, Audrey Craven, Elizabeth Cunningham, Orla Galvin, Alexandra Heumber Perry, Ericka L. Fink, Peer Baneke, Anne Helme, Joanna Laurson-Doube, Marco T. Medina, Juan David Roa, Birgit Hogl, Allan O’Bryan, Claudia Trenkwalder, Jo Wilmshurst, Rufus O. Akinyemi, Joseph O. Yaria, David C. Good, Volker Hoemberg, Paul Boon, Samuel Wiebe, J. Helen Cross, Magali Haas, Inez Jabalpurwala, Marijeta Mojasevic, Monica DiLuca, Paola Barbarino, Stephanie Clarke, Sameer M. Zuberi, Paul Olowoyo, Ayomide Owolabi, Nelson Oyesiku, Pia C. Maly-Sundgren, Bo Norrving, Surjo R. Soekadar, Pieter A. van Doorn, Richard Lewis, Tom Solomon, Franco Servadei
Journal: Nature Reviews Neurology (2023)
1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy
Authors: Qianqian Zhuang, Fengfeng Guo, Lei Fu, Yufei Dong, Shaofang Xie, Xue Ding, Shuangyi Hu, Xuanhao D. Zhou, Yangwei Jiang, Hui Zhou, Yue Qiu, Zhaoying Lei, Mengyao Li, Huajian Cai, Mingjie Fan, Lingjie Sang, Yong Fu, Dong Zhang, Aifu Lin, Xu Li, Tilo Kunath, Ruhong Zhou, Ping Liang, Zhong Liu, Qingfeng Yan
Journal: Journal of Clinical Investigation (2023)

Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young individuals. Due to heterogeneity in the clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.
Dupilumab in the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps (<scp>CRSwNP</scp>): A multicentric observational Phase IV real‐life study (<scp>DUPIREAL</scp>)
Authors: Eugenio De Corso, Ernesto Pasquini, Matteo Trimarchi, Ignazio La Mantia, Fabio Pagella, Giancarlo Ottaviano, Massimiliano Garzaro, Carlotta Pipolo, Sara Torretta, Veronica Seccia, Elena Cantone, Andrea Ciofalo, Daniela Lucidi, Gian Luca Fadda, Pia Clara Pafundi, Stefano Settimi, Claudio Montuori, Francesca Anastasi, Giulio Pagliuca, Angelo Ghidini, Carlo Cavaliere, Marianna Maffei, Francesco Bussu, Stefania Gallo, Frank Rikki Mauritz Canevari, Gaetano Paludetti, Jacopo Galli
Journal: Allergy (2023)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with significant morbidity and reduced health-related quality of life. Findings from clinical trials have demonstrated the effectiveness of dupilumab in CRSwNP, although real-world evidence is still limited.This Phase IV real-life, observational, multicenter study assessed the effectiveness and safety of dupilumab in patients with severe uncontrolled CRSwNP (n = 648) over the first year of treatment. We collected data at baseline and after 1, 3, 6, 9, and 12 months of follow-up. We focused on nasal polyps score (NPS), symptoms, and olfactory function. We stratified outcomes by comorbidities, previous surgery, and adherence to intranasal corticosteroids, and examined the success rates based on current guidelines, as well as potential predictors of response at each timepoint.We observed a significant decrease in NPS from a median value of 6 (IQR 5-6) at baseline to 1.0 (IQR 0.0-2.0) at 12 months (p < .001), and a significant decrease in Sino-Nasal Outcomes Test-22 (SNOT-22) from a median score of 58 (IQR 49-70) at baseline to 11 (IQR 6-21; p < .001) at 12 months. Sniffin' Sticks scores showed a significant increase over 12 months (p < .001) compared to baseline. The results were unaffected by concomitant diseases, number of previous surgeries, and adherence to topical steroids, except for minor differences in rapidity of action. An excellent-moderate response was observed in 96.9% of patients at 12 months based on EPOS 2020 criteria.Our findings from this large-scale real-life study support the effectiveness of dupilumab as an add-on therapy in patients with severe uncontrolled CRSwNP in reducing polyp size and improving the quality of life, severity of symptoms, nasal congestion, and smell.
Evolution of the technique of renoportal anastomosis for patients with complete portal venous occlusion in living donor liver transplantation – a retrospective cohort study
Authors: Young-In Yoon, Deok-Bog Moon, Sung-Gyu Lee, Chul-Soo Ahn, Shin Hwang, Ki-Hun Kim, Tae-Yong Ha, Gi-Won Song, Dong-Hwan Jung, Gil-Chun Park, Min-Jae Kim
Journal: International Journal of Surgery (2023)

Background: This study aimed to present our surgical technique and the long-term outcomes of living donor liver transplantations with renoportal anastomosis for patients with complete portal venous occlusion. Renoportal anastomosis (RPA) is a promising technique for portal flow reconstruction during liver transplantation in patients with complete occlusion of the portal vein and extensive splanchnic vein thrombosis. However, reports demonstrating living donor liver transplantations (LDLT) with renoportal anastomosis are rarer than those demonstrating deceased-donor liver transplantation. Materials and methods: In this single-center retrospective cohort study, we analyzed the medical records of patients who underwent portal flow reconstruction via RPA with end-to-end anastomosis between the interposition graft and LRV-connected inferior vena cava (VC) cuff. The outcomes included postoperative RPA-related morbidity and patient and allograft survival for patients who underwent LDLT with RPA. Results: Fifteen patients underwent LDLT with portal flow reconstruction via RPA from January 2005 to December 2019. The median follow-up period was 80.7 months (range: 27 d–195.2 mo). RPA evolved from end-to-end anastomosis in 1 (6.7%) patient to end-to-side anastomoses in the next 6 (40%) patients and finally, to end-to-end anastomoses between the inferior VC cuff connected to the left renal vein (LRV) and interposing vascular grafts in 8 (53.3%) patients. After standardization of the RPA technique from the eighth case in 2011, the incidence rate of RPA-related complications significantly decreased from 42.9% (3/7) to 12.5% (1/8). At the last follow-up, all 11 surviving patients had normal liver function, and 10 patients had patent anastomoses on imaging examination. Conclusions: Our standardized RPA technique using an inferior VC cuff connected to the LRV creates a safe end-to-end RPA.
Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis
Authors: Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
Journal: Journal of Clinical Investigation (2023)

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis, we studied 24 unique Collaborative Cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG, and then challenged with aerosolized M. tuberculosis. As BCG protects only half of the CC strains tested, we conclude that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to TB. T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after Mtb infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3–MAPK Signaling to Trigger Spontaneous Aortic Dissection
Authors: Ting-Ting Zhang, Qing-Qing Lei, Jie He, Xin Guan, Xin Zhang, Ying Huang, Zi-Yue Zhou, Rui-Xin Fan, Ting Wang, Chen-Xi Li, Jin-Yan Shang, Zhuo-Miao Lin, Wan-Li Peng, Li-Kai Xia, Yu-Ling He, Chuan-Ying Hong, Jing-Song Ou, Rui-Ping Pang, Xiao-Ping Fan, Hui Huang, Jia-Guo Zhou
Journal: Circulation (2023)

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell–specific and endothelial cell–specific Best3 knockout mice (Best3 SMKO and Best3 ECKO , respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3 SMKO but not Best3 ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II–infused Best3 SMKO and ApoE −/− mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3–MEKK2/3 signaling represents a novel therapeutic target for AD.
The Promise and Reality of Public Engagement in the Governance of Human Genome Editing Research
Authors: John M. Conley, R. Jean Cadigan, Arlene M. Davis, Eric T. Juengst, Kriste Kuczynski, Rami Major, Hayley Stancil, Julio Villa-Palomino, Margaret Waltz, Gail E. Henderson
Journal: The American Journal of Bioethics (2023)

This paper analyses the activities of five organizations shaping the debate over the global governance of genome editing in order to assess current approaches to public engagement (PE). We compare the recommendations of each group with its own practices. All recommend broad engagement with the general public, but their practices vary from expert-driven models dominated by scientists, experts, and civil society groups to citizen deliberation-driven models that feature bidirectional consultation with local citizens, as well as hybrid models that combine elements of both approaches. Only one group practices PE that seeks community perspectives to advance equity. In most cases, PE does little more than record already well-known views held by the most vocal groups, and thus is unlikely to produce more just or equitable processes or policy outcomes. Our exploration of the strengths, weaknesses, and possibilities of current forms of PE suggests a need to rethink both "public" and "engagement."